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Characterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.

TitleCharacterization of genetic loci that affect susceptibility to inflammatory bowel diseases in African Americans.
Publication TypeJournal Article
Year of Publication2015
AuthorsHuang C, Haritunians T, Okou DT, Cutler DJ, Zwick ME, Taylor KD, Datta LW, Maranville JC, Liu Z, Ellis S, Chopra P, Alexander JS, Baldassano RN, Cross RK, Dassopoulos T, Dhere TA, Duerr RH, Hanson JS, Hou JK, Hussain SZ, Isaacs KL, Kachelries KE, Kader H, Kappelman MD, Katz J, Kellermayer R, Kirschner BS, Kuemmerle JF, Kumar A, Kwon JH, Lazarev M, Mannon P, Moulton DE, Osuntokun BO, Patel A, Rioux JD, Rotter JI, Saeed S, Scherl EJ, Silverberg MS, Silverman A, Targan SR, Valentine JF, Wang M-H, Simpson CL, S Bridges L, Kimberly RP, Rich SS, Cho JH, Di Rienzo A, Kao LWH, McGovern DPB, Brant SR, Kugathasan S
JournalGastroenterology
Volume149
Issue6
Pagination1575-86
Date Published2015 Nov
ISSN1528-0012
Abstract

BACKGROUND & AIMS: Inflammatory bowel disease (IBD) has familial aggregation in African Americans (AAs), but little is known about the molecular genetic susceptibility. Mapping studies using the Immunochip genotyping array expand the number of susceptibility loci for IBD in Caucasians to 163, but the contribution of the 163 loci and European admixture to IBD risk in AAs is unclear. We performed a genetic mapping study using the Immunochip to determine whether IBD susceptibility loci in Caucasians also affect risk in AAs and identify new associated loci.

METHODS: We recruited AAs with IBD and without IBD (controls) from 34 IBD centers in the United States; additional controls were collected from 4 other Immunochip studies. Association and admixture loci were mapped for 1088 patients with Crohn's disease, 361 with ulcerative colitis, 62 with IBD type unknown, and 1797 controls; 130,241 autosomal single-nucleotide polymorphisms (SNPs) were analyzed.

RESULTS: The strongest associations were observed between ulcerative colitis and HLA rs9271366 (P = 7.5 × 10(-6)), Crohn's disease and 5p13.1 rs4286721 (P = 3.5 × 10(-6)), and IBD and KAT2A rs730086 (P = 2.3 × 10(-6)). Additional suggestive associations (P < 4.2 × 10(-5)) were observed between Crohn's disease and IBD and African-specific SNPs in STAT5A and STAT3; between IBD and SNPs in IL23R, IL12B, and C2orf43; and between ulcerative colitis and SNPs near HDAC11 and near LINC00994. The latter 3 loci have not been previously associated with IBD, but require replication. Established Caucasian associations were replicated in AAs (P < 3.1 × 10(-4)) at NOD2, IL23R, 5p15.3, and IKZF3. Significant admixture (P < 3.9 × 10(-4)) was observed for 17q12-17q21.31 (IZKF3 through STAT3), 10q11.23-10q21.2, 15q22.2-15q23, and 16p12.2-16p12.1. Network analyses showed significant enrichment (false discovery rate <1 × 10(-5)) in genes that encode members of the JAK-STAT, cytokine, and chemokine signaling pathways, as well those involved in pathogenesis of measles.

CONCLUSIONS: In a genetic analysis of 3308 AA IBD cases and controls, we found that many variants associated with IBD in Caucasians also showed association evidence with these diseases in AAs; we also found evidence for variants and loci not previously associated with IBD. The complex genetic factors that determine risk for or protection against IBD in different populations require further study.

DOI10.1053/j.gastro.2015.07.065
Alternate JournalGastroenterology
PubMed ID26278503
PubMed Central IDPMC4685036
Grant ListAI067068 / AI / NIAID NIH HHS / United States
AR-62278 / AR / NIAMS NIH HHS / United States
DK046763-19 / DK / NIDDK NIH HHS / United States
DK062413 / DK / NIDDK NIH HHS / United States
DK062420 / DK / NIDDK NIH HHS / United States
DK062422 / DK / NIDDK NIH HHS / United States
DK062423 / DK / NIDDK NIH HHS / United States
DK062429 / DK / NIDDK NIH HHS / United States
DK062431 / DK / NIDDK NIH HHS / United States
DK062432 / DK / NIDDK NIH HHS / United States
DK087694 / DK / NIDDK NIH HHS / United States
HL06957 / HL / NHLBI NIH HHS / United States
HS021747 / HS / AHRQ HHS / United States
M01-RR-00032 / RR / NCRR NIH HHS / United States
N01-AR-02247 / AR / NIAMS NIH HHS / United States
P01 AR49084 / AR / NIAMS NIH HHS / United States
R01 DK087694 / DK / NIDDK NIH HHS / United States
U01 DK062418 / DK / NIDDK NIH HHS / United States
U01 DK062420 / DK / NIDDK NIH HHS / United States
U01 DK062431 / DK / NIDDK NIH HHS / United States
U54DE023789-01 / DE / NIDCR NIH HHS / United States